Orforglipron Maintains Weight Loss After Injectable Therapy
Key Takeaways
- Greater maintenance of prior weight loss was observed with once-daily oral orforglipron than placebo in both prior-injectable cohorts.
- All key secondary endpoints were met, including maintenance of at least 80% of the earlier weight reduction.
- Gastrointestinal events were the most common adverse events, were mostly mild to moderate, and led to discontinuation in a minority of orforglipron-treated participants without a reported liver safety signal.
ATTAIN-MAINTAIN consisted of two phase 3b randomized, double-blind, placebo-controlled cohorts at 29 U.S. sites, analyzed separately after completion of SURMOUNT-5. Eligible participants were adults with obesity or body mass index at least 27 kg/m2 with obesity-related complications, without diabetes, and with at least 5% body weight reduction at week 72. Cohort 1 randomized 125 participants to orforglipron and 80 to placebo, while cohort 2 randomized 105 to orforglipron and 66 to placebo. The first dose was ideally given within 14 days of the last SURMOUNT-5 dose, then escalated from 12 mg daily every 4 weeks to 36 mg or the maximum tolerated dose during a 52-week treatment period with 2-week safety follow-up. Placebo participants could begin rescue orforglipron at week 24 after regaining at least 50% of prior weight loss, and the primary endpoint was percent maintenance of body weight reduction among plateau participants.
In cohort 1, participants who reached a body-weight plateau maintained 74.7% of prior weight loss with orforglipron and 49.2% with placebo, a treatment difference of 25.5 percentage points. The 95% confidence interval was 14.5 to 36.5, and the between-group difference met statistical significance with P<0.001. In cohort 2, the corresponding values were 79.3% and 37.6%, yielding a 41.7 percentage point difference with a 95% confidence interval of 24.4 to 59.0 and P<0.001. Maintenance of at least 80% of prior weight reduction occurred in 43.7% versus 16.4% in cohort 1 and 55.0% versus 6.9% in cohort 2, with both comparisons meeting P<0.001. All key secondary endpoints were met, and waist circumference plus selected cardiometabolic measures remained improved after the switch.
The most common adverse events were gastrointestinal, including nausea, constipation, vomiting, and diarrhea, and these events were mostly mild to moderate. During the first 4 weeks after transition, gastrointestinal events occurred in 10.5% of participants in cohort 1 and 9.5% in cohort 2, with no dose de-escalations after direct transition to 12 mg. Discontinuations because of adverse events ranged from 4.8% to 7.3% across the orforglipron groups. Serious adverse events were uncommon, including one adjudicated mild pancreatitis case in cohort 1 and one death in cohort 2 that investigators did not consider treatment related. Alanine and aspartate aminotransferase elevations occurred in small numbers, and no liver safety signal was detected. Overall, the safety profile was dominated by gastrointestinal events rather than a new major signal.
The trial did not include a comparator arm that continued injectable obesity medication, so it does not address whether switching to oral therapy matches continued tirzepatide or semaglutide. Other limitations included the 1-year duration, the predominantly white population enrolled only in the United States, and cardiometabolic analyses that were exploratory or planned for fuller future reporting. Across both cohorts, adults with prior injectable incretin-associated weight loss preserved more of that loss over 52 weeks with oral orforglipron than with placebo.